The prototype atypical neuroleptic, clozapine, is notable for its enhanced therapeutic in otherwise treatment resistant patients with schizophrenia. We observed in our initial study that over a third of patients respond more favorably to clozapine than to the typical neuroleptic, fluphenazine. We have focused on mechanisms of action of the atypical neuroleptic by addressing clozapine's diverse pharmacologic effects using an array of biological techniques. We observed in vivo "markers" of dopaminergic antagonist effects, serotonergic antagonist effects and enhancement of norepinephrine release. Predictors of clozapine response include high EPS during typical neuroleptic treatment, low plasma HVA during clozapine treatment and enhanced serotonergic responsivity in a drug-free state. In further work, we have applied functional brain imaging, PET and SPECT to discern distinct metabolic effects of clozapine and relationship to D2 receptor blockade and clinical response. Future plans involve the extension of the data base to include 50 patients and further studies to identify clinical and biological predictors of response.